There has been a movement afoot to clarify the role of drug product dissolution testing within the new world of Quality by Design, and to use QbD principles to take a fresh look at how such testing can be improved for the betterment of product development. An AAPS focus group has taken the lead on this initiative, and has published a position paper stating its case (link below): In vitro dissolution testing is old school and is not necessarily a good predictor of in vivo results. Quality by Design and the increasing use of the biopharmaceutical classification system (BCS) provide an opportunity for the industry to rethink the value of dissolution testing and use a revamped testing methodology to improve overall drug development.

PharmaQbD interviewed Dr. Raimar Löbenberg, an associate professor at the University of Alberta, Canada, and one of the authors of the recent AAPS position paper.

PQbD: You say that there’s always been an “organizational problem” that has hindered product lifecycle development in the pharmaceutical industry. Are you seeing clear signs of change—and is QbD having its desired effect?

R.L.: QbD is a concept which is inclusive rather than exclusive. For pharmaceutical development I believe we have to change many company traditions and reporting structures. A real QbD should ideally include marketing and reimbursement strategies as well as formulation and process controls because these parameters might impact the final product, too.

For the pharmaceutical R&D part of product development, QbD will require effective communications between the different research units. One of the most important factors for companies who want to start with QbD is to define and outline their current knowledge space in product development. Here the lessons learned from failed projects and what worked well in the past can be instrumental for the overall set-up of a QbD project. I think that this will be, for many companies, a bigger challenge than the actual science and to define the control spaces.

PQbD: Where is current dissolution testing lacking, in your opinion?

R.L.: Dissolution testing is probably one of the most misunderstood performance tests. It is just not right that an in vitro test in a vessel with some buffer and stirrer has anything to do with the performance of the drug in a biological system. The few cases where the in vitro dissolution is a surrogate for the in vivo behavior is rather a lucky “accident”. I think we need for most products two different dissolution tests—one for daily use and one for IVIVC [in vivo–in vitro correlations] and SUPAC [scale-up post approval changes]. For batch release you want something fast, robust and easy to validate. Most biorelevant media do not qualify for such an approach. However, in the last years we have seen more and more examples of how biorelevant conditions can be used to establish IVIVCs.

PQbD: How does dissolution testing fit into the framework of Quality by Design, and how might QbD benefit and change the way testing is done?

R.L.: QbD might change how products are released in the future. Instead of end product testing we might have in-process testing of critical variables and, due to the design and quality system, a tablet can be released because the processes it went through are sufficiently controlled and a product with known properties is the output. Batch release is then not required but it will take quite some work to demonstrate that the properties of the product are known and according to specification.

PQbD: You’re suggesting that QbD is a way of making in vivo and in vitro testing more consistent and reflective of each other. Can you elaborate upon this?

R.L.: As mentioned before, in vitro testing does not necessarily have anything to do with in vivo performance. Dissolution tests which aim to mimic the GI passage are more complex and if the right parameters are used, then it can be quite useful to understand what happens in vivo. Such methods might be used to optimize absorption patterns in the intestine. The biggest challenge is then to link such complex tests with conventional dissolution profiles.

PQbD: How can QbD help to facilitate and optimize dissolution testing as a product moves from early- to late-stage manufacturing?

R.L.: QbD might utilize dissolution testing to demonstrate that it is not needed as a QC test for a specific product for batch release. For example, if the dissolution of a drug can be linked to surface area, particle size distribution and shape, then control of these parameters might be more meaningful than a dissolution test at the end of production.

PQbD: QbD might also enable related or surrogate tests to be performed to control the critical quality attributes of the product. What sort of tests might those be?

R.L.: As mentioned before, other API attributes might be the source of deviations form the specifications and must be controlled, like surface area or shape. If such parameters are known and are controlled, then a simple disintegration test might be needed to demonstrate that the dosage form disintegrates and the rest is controlled by the API properties—e.g., dissolution rate. In QbD there must be a rationale for a specification. This rationale must be justified and will help to select the most appropriate test method or will give the rationale why a traditional performance test like dissolution testing might be waived for a disintegration test.

PQbD: Let’s talk about the BCS—what are the limitations of the system as it stands?

R.L.: The biggest obstacle is again perceptions and misunderstanding. The classification was originally meant for APIs but we now see that formulation can move a drug from a class 2 into class 1 but the regulators might not give such a drug a biowaiver. We need in vivo data confirming the in vitro science, but this is mostly the confidential information of a drug submission.

Another area has to do with borderline drugs between classes. Here in vivo data and the supporting science are needed to understand and classify them correctly. On the other hand, the introduction of the Biopharmaceutical Drug Disposition Classification System was a good addition to the BCS. It helps to classify the absorption properties of drugs if other test methods give inconclusive data.

PQbD: Despite its limitations, you see the BCS as a suitable mechanistic foundation for QbD. Explain this in brief.

R.L.: The BCS is a mechanistic way to determine oral absorption and deals with the main parameters solubility and permeability. QbD is a mechanistic approach to assure product quality by controlling critical processes or variables. QbD is not possible for a pharmaceutical product without using the basic mechanistic principles of the BCS.

PQbD: QbD might be a means to waive in vivo bioequivalence studies in situations where the product has been altered in late-stage development. Could you present a scenario for this?

R.L.: Normally QbD should have taken care of major changes or problems early on in the development process. But let’s assume your excipient supplier changes the specifications of his excipient. Now depending on your product specifications, such excipient changes might be within your specifications; if not, then you must show that the new formulation performs equally to the previous product. If the dissolution behavior was linked to an API attribute like particle size or surface area rather than to the entire formulation, then your new formulation might qualify for a biowaiver since the change does not impact the attribute which was identified as critical. I see QbD as a product specific extension of SUPAC when it comes to biowaivers.

PQbD: Software and today’s improved capabilities for measuring Critical Quality Attributes are fundamental to this discussion. How important is it that companies take advantage of current tools at their disposal?

R.L.: Today there are plenty of models and software available. It depends highly on the complexity of the product you want to develop. Software simulations can be of great value to set dissolution specifications for drugs. They can also help to optimize release profiles for drugs to improve their bioavailability. All this can be done by simulations and if the clinical data confirm the predicted ones then one can use the simulation parameters to define the acceptable ranges for a product to be bioequivalent to its bio batch.

PQbD: You’ve been part of the AAPS focus group. What’s the status of the group’s work, and what is left to accomplish?

R.L.: The focus group is very active and it is an ongoing process. In 2009, the group published a position paper on the role of dissolution testing  in product development. The group organized two workshops, one in India in  May and one in South Africa in December. Besides this, we plan to have a face-to-face meeting later this year. The next target is the program planning for the upcoming AAPS 2010 meeting.

Related Resources

Position Paper: The Value of In Vitro Dissolution in Drug Development
http://pharmtech.findpharma.com/pharmtech/Peer-Reviewed+Research/The-Val...

AAPS In Vitro Release and Dissolution Testing Focus Group
http://www.aapspharmaceutica.com/inside/focus_groups/InVitro/index.asp

Dissolution Testing and Quality by Design (QbD): Research Summary and List of Key References
http://www.scitopics.com/Dissolution_Testing_and_Quality_by_Design_QbD.h...